Studies in organic synthesis

本世纪在完全合成复杂的天然产品和相关化合物方面的最终挑战是能够揭穿这样的神话，即这些化合物在制药工业中不是经济上可行的目标(S.Baran)。J.组织化学。2010、75、4657)。 因此，我们目前正在探索一种强大的合成环加成反应的通用性，用于快速构建天然和非天然类固醇和高级萜类化合物。我们实验室发现的这种基于阴离子的环加成反应，通过将两个构筑单元(单环或双环)与手性完全控制相结合，一步或两步得到多环化合物。由于高度收敛，这种新的合成策略可以用于目标定向合成选定的天然产物以展示其价值，然后用于多样性定向合成以在工业上发现新的生物活性化合物。 为了展示这一新策略的潜力，我们最近报道了第一个哇巴因(Angew.化学。内部艾德。2008、47、1272)。这种复杂的心脏活性类固醇最近被确认为一种人类内源性激素，与高血压有直接联系。这一新的化学知识导致了高血压研究项目和内源性哇巴因生物合成途径的研究。我们还完成了马尿醇的全合成，这是一种可能导致开发基于新机制的抗癌药物的类固醇。我们还在研究抗癌剂布鲁替丁、神经毒素蝙蝠毒素、抗癌剂紫杉醇及其相关类似物的合成。 我们还重新燃起了兴趣，研究立体电子效应的新方面与大量有机官能团的构象和反应活性的关系。

The ultimate challenge of this century in total synthesis of complex natural products and related compounds is to be able to debunk the myth that such compounds are not economically viable targets in the pharmaceutical industry (S. Baran. J. Org. Chem. 2010, 75, 4657). Accordingly, we are currently exploring the generality of a powerful synthetic cycloaddition reaction for the rapid construction of natural and non-natural steroids and higher terpenoids. This novel anionic-based cycloaddition reaction discovered in our laboratory leads to polycyclic compounds in one or two-steps by combining two building blocks (mono or bicyclic) with complete control of chirality. Being highly convergent, this new synthetic strategy can be used for target-oriented synthesis of selected natural products to demonstrate its value and later on for diversity oriented synthesis for the discovery of new biological active compounds in industry. In order to demonstrate the potential of this novel strategy, we have recently reported the first total synthesis of Ouabain (Angew. Chem. Int. Ed. 2008, 47, 1272). This complex cardioactive steroid recently being identified as a human endogenous hormone has a direct link with hypertension. This novel chemical knowledge has led to the elaboration of research project on hypertension and on the study of the biosynthetic pathway of endogenous Ouabain. We have also completed the total synthesis of Hippuristanol, a steroid that could lead to develop novel-mechanism-based anticancer drugs. We are also working on the synthesis of the anticancer agent, Bruceantin, the neurotoxin Batrachotoxin, the anticancer agent Taxol and related analogues. We have also a renewed interest to investigate novel aspect of stereoelectronic effects in relation with conformation and reactivity of a large number of organic functional groups.